The present invention relates to coatings and medical devices that deliver therapeutic amounts of nitric oxide (NO) to areas where NO dosing is indicated. More particularly, the present invention relates to fibrous materials that evolve nitric oxide after a delayed activation. The nanofibers of the present invention function to both carry and sequester reagents, which can react to release NO gas, when water, blood or other fluids known as activators are brought into contact with the nanofiber. The sequestration action slows the diffusion of activators to an NO precursor and thus delays the precursor's conversion to NO.
NO is known to inhibit the aggregation of platelets and to reduce smooth muscle proliferation, which is known to reduce restenosis. When delivered directly to a particular site, it has been shown to prevent or reduce inflammation at the site where medical personnel have introduced foreign objects or devices into the patient, such as stents or other implantable devices.
Researchers have sought various ways to deliver NO to damaged tissue and to tissues and organs at risk of injury. NO can be delivered systemically, but such delivery can bring undesired side effects with it U.S. Pat. No. 5,814,656. Ideally, NO should be delivered in a controlled manner specifically to those tissues and organs that have been injured or are at risk of injury. The present invention fills this need by providing a coatings and medical devices that release NO after a delay, which gives the physician time to implant the device. Thus, for the most part only tissues requiring NO treatment receive doses of NO.
Insoluble polymeric NONOates have also been generally described in Smith et al. U.S. Pat. No. 5,519,020 to topically deliver NO to specific tissues. However, this patent does not discuss impeding activation such that there is substantially a delay between the time the device is first applied and the time when NO production becomes significant. The use of polymeric NONOates as coatings on implantable medical devices is also disclosed in Stamler et al. U.S. Pat. No. 5,770,645. This patent is similarly deficient in that it too fails to discuss any mode of delaying nitric oxide production. The device of ‘645 is essentially active from the moment it is first implanted because it lacks an activator-impeding element. In contrast, the present invention incorporates just such an element, which is specifically directed to slowing or delaying the activation of the nitric oxide predrug.
Probably, the most closely related art is the inventors' own U.S. Pat. No. 6,737,447, which discloses a polymeric coating for medical devices that releases nitric oxide in a controlled manner. However, the distinction between this and the present invention is that ‘447’s mode of controlled release is its use of bisepoxide to crosslink the coating thus constricting that material's porosity thus slowing the diffusion of activators into and nitric oxide out of the coating. In contrast the present invention utilizes a second fiber having either a more hydrophobic character, or a buffering effect to impede, slow or delay the activation of the nitric oxide precursor.